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Sex-related variations in the response of drug therapies targeting purinergic signaling pathways in sepsis

Award Number: R21AI156627
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 04/12/2021
PERIOD OF PERFORMANCE END DATE: 03/31/2024

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Sex-related variations in the response of drug therapies targeting purinergic signaling pathways in sepsis - Sex-related variations in the response of anti-platelet drug therapies targeting purinergic signaling pathways in sepsis Sepsis, a complex clinical syndrome resulting from a serious infection, is a major healthcare problem associated with high morbidity and mortality. Current sepsis treatments are limited to supportive therapies, and specific pharmacologic treatments that could greatly improve patient outcomes have not yet been developed With hospital mortality rates of affected patients reportedly as high as 50%, there is a critical need for improved methods for treating sepsis. Sex differences in the morbidity and mortality of sepsis have been observed in various clinical studies and animal models. To date, females has shown less mortality and decreased organ failure in mice and humans compared to their male counterpart but the lack of studies comparing both genders limits our capacity to evaluate the extent of sex-related differences. However, the data obtained so far suggest that sex should be taken into account when identifying the optimal pharmacological intervention for sepsis. Our previous studies have shown that in male mice, anti-platelet therapy that targets the ADP-receptor P2Y12 improves the outcome of sepsis. However, targeting another platelet ADP-receptor, P2Y1 did not seem to alter sepsis. Previous data have shown that the signaling of the P2Y1 and P2Y12 activation and intracellular are complex and sex-specific in platelets, however the data are still unclear. We are lacking similar information in other cells of the immune system. No studies have investigated sex-related differences in targeting purinergic signaling during sepsis. Hence this project aims to investigate sex-related differences in how the purinergic signaling pathways of activated platelets respond to drug therapies used for treating sepsis. We will use a well-established murine model of sepsis such as cecal ligation and puncture in male and female P2Y12 knock-out (KO) and P2Y1 KO mice and compared them with wild-type. We will analyze the outcome of sepsis in terms of survival, organ dysfunction, plasma cytokine levels, as well as platelet functions, such as platelet-leukocyte interaction, platelet adhesion markers and platelet reactivity. The data obtained in this study will provide 1) a more comprehensive understanding of sex-related differences in platelet behavior during sepsis between male and female mice, 2) the efficacy and safety of anti-platelet drugs in male and female.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2025 ( Subtotal = $0 )
2025	2022	NORTH DAKOTA STATE UNIVERSITY	1301 12TH AVE N	FARGO	ND	58102	CASS	USA	Allergy and Infectious Diseases Research	000	2	10/29/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2022 ( Subtotal = $181,250 )
2022	2022	NORTH DAKOTA STATE UNIVERSITY	1919 UNIVERSITY DR N, STE 102	FARGO	ND	58102	CASS	USA	Allergy and Infectious Diseases Research	000	2	3/10/2022	NON-COMPETING CONTINUATION	$181,250
														Subtotal = $181,250

Issue Date FY: 2021 ( Subtotal = $217,500 )
2021	2021	NORTH DAKOTA STATE UNIVERSITY	1919 UNIVERSITY DR N, STE 102	FARGO	ND	58102	CASS	USA	Allergy and Infectious Diseases Research	000	1	4/12/2021	NEW	$217,500
														Subtotal = $217,500

Grand Total All Awards = $398,750

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Sex-related variations in the response of drug therapies targeting purinergic signaling pathways in sepsis

Award Number: R21AI156627

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 04/12/2021

PERIOD OF PERFORMANCE END DATE: 03/31/2024

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